We study HIV and SIV variants that have the Rev/RRE regulatory system replaced by CTE with the goal to evaluate their pathogenicity. Attenuated virus strains have been shown to be effective in protecting against virus challenge, but the strains studied so far have also been shown to be associated with pathogenicity. We found that the SIV variant virus can persistently infect rhesus macaques (von Gegerfelt A, et al: J Virol 73:6159-65, 1999). Therefore, the replacement of the essential Rev regulation by the CTE generated a virus variant that retained its replicative capacity both in vitro and in vivo, albeit at low levels. Infection of neonate and juvenile macaques by the Rev-independent SIV strains did not induce any signs of immune disfunction or disease during the 1-3 years of follow-up. These data demonstrate that Rev/RRE regulatory mechanism is required for high levels of virus propagation and that this control mechanism plays an important role in the pathogenicity of SIV. The replacement of Rev/RRE by the hTAP/CTE system provides a novel approach to lower the virulence of a pathogenic lentivirus.